The changing in vitro susceptibility pattern to pyrimethamine/sulfadoxine in Plasmodium falciparum field isolates from Kilifi, Kenya.

Abstract

Abstract. Two clinical trials that used Falcidin (Cosmos Ltd., Nairobi, Kenya), the antifolate combination of pyrimethamine/sulfadoxine (PM/SD), as treatment for non-severe falciparum malaria in children at Kilifi, Kenya in 1987 have presented an opportunity to assess in vitro the susceptibility trend of Plasmodium falciparum to PM and SD over time on the Kenya coast. The first set of isolates was collected prior to the introduction of PM/SD into the Kenya Medical Research Institute/Wellcome Trust Research unit while the second set was taken soon after PM/SD was introduced in the study area as the first-line treatment drug for uncomplicated falciparum malaria. In the first trial, 69 isolates collected before and after treatment of malaria with PM/SD were tested directly in the field for susceptibility to PM and SD using the standard in vitro micro-test technique, with minimal levels of folate. In the second trial, 97 isolates similarly collected were adapted to culture, and tested as described elsewhere. In both studies, PM and SD susceptibility tests were done separately. There was a highly significant decrease (P Ͻ 0.01) in the in vitro sensitivity of P. falciparum isolates to PM and SD between the two trials. In the first trial, the isolates were either sensitive to both PM and SD or resistant to PM and sensitive to SD. During the second trial, isolates were either resistant to PM and sensitive to SD or resistant to both drugs. These results are important in estimating the useful therapeutic life (UTL) of PM/SD in this area and in identifying alternative antifolate drugs.

Plasmodium falciparum Isolates in India Exhibit a Progressive Increase in Mutations Associated with Sulfadoxine-Pyrimethamine Resistance

“…It seems that a mutation in the sequence for DHFR occurs first, followed by a mutation in the sequence for DHPS, because group A isolates already had higher rates of mutations in the DHFR sequence than in the DHPS sequence. This is in agreement with information in the literature that DHFR mutations occur first under the influence of SP treatment (20,40).…”

“…The absence of multiple mutations in the genes for both enzymes is an indication that resistance has not yet reached such an alarming level that SP treatment failures are occurring in India. The results suggest, however, that with continued drug pressure in the field, the mutation rate will increase further, which will lead to SP treatment failures, as seen elsewhere in the world (4,6,20,25,39,40).…”

Frequency Distribution of Antimalarial Drug Resistance Alleles among Plasmodium falciparum Isolates from Gezira State, Central Sudan, and Gedarif State, Eastern Sudan

“…[6][7][8][9][10] In particular, a combination of five point mutations, pfdhfr N51I, C59R, S108N, and pfdhps A437G and K540E, have been shown to be strongly associated with sulfadoxine/pyrimethamine (SP) resistance in Africa. [11][12][13] Adding artemisinin derivatives (i.e., artesunate) to standard antimalarial drugs (i.e., SP) is a strategy to reduce treatment failure and transmission potential, because artemisinin derivatives act rapidly and kill malaria parasites that are resistant to other drugs. 14 In fact, many malaria endemic countries have lately adopted artemisinin-based combination therapy (ACT) as the first-line drug for treating uncomplicated malaria, as recommended by the World Health Organization (WHO).…”

Comparative Efficacy of Aminoquinoline-Antifolate Combinations for the Treatment of Uncomplicated Falciparum Malaria in Kampala, Uganda

“…Indeed, evidence for increasing SP resistance in East Africa has begun to emerge. [3][4][5][6] Countries faced with a high prevalence of CQ-resistant malaria are increasingly considering the use of combination therapy to treat uncomplicated malaria. Combination therapy has been advocated to improve efficacy and delay the development and spread of drug resistance.…”